Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety. Full citations for publications not cited fully within the specification are set forth at the end of the specification.
Hemorrhagic stroke accounts for approximately 15% of all strokes but is associated with a disproportionate degree of morbidity. Studies have indicated that inflammatory processes and complement activation in particular may be involved in exacerbating brain injury after the hemorrhagic event (Hua Y, et al., 2000, J Neurosurg. 92: 1016-1022). Early attempts at complement inhibition using cobra venom factor, C1-esterase inhibitor, and soluble complement receptor-1 revealed reduced edema formation in hemorrhagic models (Xi G, et al., 2001, Stroke 32: 162-167; Xi G, et al., 2002, Acta Neurochir Suppl. 81: 253-256) and decreased infarct volumes in animal stroke models (Figueroa E, et al., 2005, Neurosci Lett. 380: 48-53; De Simoni M G, et al., 2003, J Cereb Blood Flow Metab. 23: 232-239; Vasthare U S, et al., 1998, Brain Res Bull. 45: 413-419). However, the lack of specificity of these agents left it unclear as to which complement components are most relevant in the pathogenesis of cerebral injury.
C3a and C5a, collectively known as the anaphylotoxins, induce a wide variety of cellular responses, including chemotaxis, degranulation, oxidative bursts, and disruption of the blood brain barrier (Elsner J, et al., 1994, Blood 83: 3324-3331; Soruri A, et al. 2003, J. Immunol. 170: 3306-3314; Stahel P F, et al., 1998, Brain Res Rev. 27: 243-256). Recent studies have revealed that functional inhibitors as well as genetic knockouts of C3 were protective against and ICH-induced edema (Yang S, et al., 2006, J Cereb Blood Flow Metab. 26: 1490-1495) and cerebral ischemic/reperfusion injury (Motto J, et al., 2006, Circ Res. 99: 209217; Ducruet A F, et al., 2008, J Cereb Blood Flow Metab. 28: 1048-1058; Atkinson C, et al., 2006, J. Immunol. 177: 7266-7274).
However, attempts to inhibit C5 have met with conflicting results. Genetic knockouts of C5 have shown increased vulnerability to ICH (Nakamura T, et al., 2004, J Cereb Blood Flow Metab. 24: 487-494), ischemic stroke (Yang et al., 2006, supra), and excito-toxic injury (Pasinetti G M, et al., 1996, Neurobiol Dis. 3: 197-204). In contrast, functional inhibition of C5 and the C5a receptor have shown neuro-protection against ischemia-reperfusion injury in MCAO models (Costa C, et al., 2006, Brain Res. 1100: 142-151) as well as visceral (Fleming S D, et al., 2003, Clin Immunol. 108: 263-273; Wada K, et al., 2001, Gastroenterology 120: 126-133) and renal models (de Vries B, et al., 2003, J Immunol. 170: 3883-3889; Bao L, et al., 2005, Eur J. Immunol. 35: 2496-2506; Heller T, et al., 1999, J Immunol. 163: 985-994; Arumugam T V, et al., 2003, Kidney Int. 63: 134-142).
Intracerebral hemorrhage (ICH) is a devastating disease process, which has a 30-50% mortality rate that has not improved over the past two decades. Currently available therapies are limited to supportive medical therapy and surgery for only a select group of patients. Thus, there is a need in the art to identify and develop new therapies for the treatment of ICH. This invention addressed those needs.